Advances and Challenges of HDAC Inhibitors in Cancer Therapeutics

Abstract

Since the identification and cloning of human histone deacetylases (HDACs) and the rapid approval of vorinostat (Zolinza®) for the treatment of cutaneous T-cell lymphoma, the field of HDAC biology has met many initial successes. However, many challenges remain due to the complexity involved in the lysine posttranslational modifications, epigenetic transcription regulation, and nonepigenetic cellular signaling cascades. In this chapter, we will: review the discovery of the first HDAC inhibitor and present discussion regarding the future of next-generation HDAC inhibitors, give an overview of different classes of HDACs and their differences in lysine deacylation activity, discuss different classes of HDAC inhibitors and their HDAC isozyme preferences, and review HDAC inhibitors' preclinical studies, their clinical trials, their pharmacokinetic challenges, and future direction. We will also discuss the likely reason for the failure of multiple HDAC inhibitor clinical trials in malignancies other than lymphoma and multiple myeloma. In addition, the potential molecular mechanism(s) that may play a key role in the efficacy and therapeutic response rate in the clinic and the likely patient population for HDAC therapy will be discussed.

Keywords: Acetylation; Acylation; Amino-benzamide; Benzamide; Clinical trials; Depsipeptide; HDAC inhibitor; Histone deacetylase; Hydrazide; Hydroxamic acid; Lysine; NCI 60 cell line screen; Pharmacokinetics; Posttranslational modification; Short-chain fatty acid; Sirtuin; Tetrapeptide; p53.